EP1235574B1 - Methods for making sustained-release pharmaceutical compositions of ergot alkaloids having improved bioavailability and compositions thereof - Google Patents

Methods for making sustained-release pharmaceutical compositions of ergot alkaloids having improved bioavailability and compositions thereof Download PDF

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EP1235574B1
EP1235574B1 EP00985142A EP00985142A EP1235574B1 EP 1235574 B1 EP1235574 B1 EP 1235574B1 EP 00985142 A EP00985142 A EP 00985142A EP 00985142 A EP00985142 A EP 00985142A EP 1235574 B1 EP1235574 B1 EP 1235574B1
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release
dihydroergocryptine
sustained
bioavailability
ergot
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EP1235574A2 (en
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Federico Mailland
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Polichem SA
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Polichem SA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • This invention relates to methods for making sustained-release pharmaceutical compositions of ergot alkaloids, and particularly to methods for making sustained-release pharmaceutical compositions of ergot alkaloids having improved bioavailability.
  • ergot alkaloids can be classified according to their different chemical structures, for example ergolines, lysergic acid derivatives, ergot peptide alkaloids and dihydrogenated ergot peptide alkaloids.
  • Clinical applications of ergot alkaloids and their derivatives include treatment of Parkinson's disease, migraine headaches, hyperprolactinemia and cerebro-vascular disturbances, just to name a few.
  • U.S. Patent No. 3,896,228 to Richardson discusses the use of ergot alkaloids to increase urine volume and urine pH.
  • U.S. Patent No. 3,987,173 to Borredon proposes the use of certain mixtures of vincamine and ergot alkaloids to treat blood circulation disorders.
  • U.S. Patent No. 4,229,451 to Fehr et al. provides ergopeptine derivatives useful as venoconstrictors and venotonics.
  • U.S. Patent No. 4,315,937 to Maclay et al. discusses ergots and their use in treating minimal brain dysfunction.
  • U.S. Patent No. 4,440,722 to Djorjevic et al. provides a medicine containing salts of ergotamine, ergosinine, ergocryptinine, ergocristinine and ergocominine used for treating arterial hypertension, heart insufficiency, heart arrhythmia or cephalalgia.
  • U.S. Patent No. 4,462,983 to Azria et al. proposes the use of certain ergot peptide alkaloids adapted for nasal or pulmonary administration.
  • ergot alkaloids The pharmacological actions of ergot alkaloids are varied and complex, but in general appear to result from their actions at adrenergic, dopaminergic and serotoninergic receptors. The spectrum of effects depends on the agent, dosage, species, tissue, and experimental or physiological conditions. In general, ergot alkaloids are characterized by erratic absorption and a high hepatic first pass effect with wide biotransformation. More specifically, gastrointestinal absorption of ergot alkaloids is low, due to the high hepatic first pass, and sometimes erratic. Moreover, the administration of ergot alkaloids can occasionally be associated with adverse events, particularly vascular and cardiac.
  • Drugs such as ergot alkaloids, that are susceptible to high hepatic clearance may need to be administered in higher doses in order to maintain blood concentrations above the minimum effective concentration for a sufficient amount of time to provide the desired pharmacological effect.
  • the burst of drug absorption that occurs just after its administration may cause blood concentrations to exceed the minimum toxic concentration.
  • One method of avoiding this deleterious effect is to employ lower dosage levels with more frequent dosing. Frequent dosing is not an ideal solution, however, because of the inconvenience, the increased cost and the increased likelihood that the patient will forget to take the proper number of doses.
  • Another method of keeping drug concentration on a narrow therapeutically active level is to administer the drug using sustained-release drug delivery systems.
  • Sustained-release drug delivery systems include any drug delivery system that achieves slow release of the drug over an extended period of time.
  • Controlled-release systems maintain constant drug levels in the target tissue or cells.
  • Prolonged-release systems are unable to maintain a constant drug level, but nevertheless prolong the therapeutic blood or tissue level of the drug for an extended period of time.
  • sustained-release delivery systems have been proposed for a number of different drugs.
  • U.S. Patent No. 4,389,393 to Schor et al. proposes sustained release therapeutic compositions based on high molecular weight hydroxypropylmethylcellulose.
  • U.S. Patent No. 5,069,911 to Züger proposes a controlled release formulation for oral administration of a 9, 10-dihydro ergot alkaloid,
  • U.S. Patent No. 5,128,142 to Mulligan et al. proposes a controlled release formulation that includes an absorbate of a mixture of a pharmaceutically useful active ingredient and an inactive substance adsorbed on a cross-link polymer.
  • a method of improving bioavailability of ergot derivatives administered using sustained-release delivery systems comprising combining an ergot derivative or mixture thereof with a pharmaceutically acceptable hydrophilic swelling agent or mixture thereof and one or more pharmaceutically acceptable excipients, wherein the ergot derivative has the formula wherein R 1 is hydrogen or halogen, R 2 is hydrogen or C 1 -C 4 alkyl, R 3 is isopropyl, sec.-butyl, isobutyl or benzyl, R 4 is methyl, ethyl, isopropyl, and mixtures thereof, and either R 5 is hydrogen and R 6 is hydrogen or methoxy, or R 5 and R 6 together is an additional bond, and mixtures thereof, said method being characterized in that the ratio of said ergot derivative to said hydrophilic swelling agent is 1:0.5 to 1:10.
  • a pharmaceutical composition comprising ⁇ -dihydroergocryptine may also be provided.
  • the composition has a bioavailability at least equal to the bioavailability of the ergot derivative or mixture thereof administered using a conventional delivery system.
  • Methods and pharmaceutical compositions according to the present invention may therefore provide sustained-release characteristics while improving the bioavailability of ergot derivatives.
  • the present invention provides a sustained-release composition of ergot derivatives having an improved bioavailability over conventional compositions.
  • the sustained-release composition of the present invention comprises an ergot derivative or mixture thereof, a pharmaceutically acceptable swelling agent or mixture thereof, and one or more pharmaceutically acceptable excipients.
  • bioavailability is defined as the total amount of drug systemically available over time. Bioavailability may be determined by measuring total systemic drug concentrations over time after administration of a sustained-release composition of the present invention and after administration of a conventional release composition. The improved bioavailability is defined as an increase in the Area Under the Curve (AUC). AUC is the integrated measure of systemic drug concentrations over time in units of mass-time/volume. Following the administration of a drug dose, the AUC from the time of dosing to the time when no drug remains in the body, is a measure of the exposure of the patient to the drug.
  • AUC Area Under the Curve
  • Ergot derivatives of the present invention have the formula: wherein R 1 is hydrogen or halogen, R 2 is hydrogen or C 1 -C 4 alkyl, R 3 is isopropyl, sec.-butyl, isobutyl or benzyl, R 4 is methyl, ethyl, isopropyl, and mixtures thereof, and either R 5 is hydrogen and R 6 is hydrogen or methoxy, or R 5 and R 6 together is an additional bond, and mixtures thereof. or mixtures thereof.
  • R 1 is halogen, it is preferably bromine.
  • Preferred compounds of Formula I are those in which R 1 , R 5 and R 6 are hydrogen, R 2 is methyl, and R 4 is isopropyl or methyl, provided that R 4 is methyl only when R 3 is benzyl.
  • R 1 bromine
  • R 2 methyl
  • R 3 isobutyl
  • R 4 isopropyl
  • R 5 and R 6 are a second bond.
  • Suitable salt forms are salts of pharmacologically acceptable acids; for example, the methanesulfonate, maleate and tartrate salt forms.
  • the most preferred compound is dihydroergocriptine, usually employed in the form of mesylate. It is indicated for use in the treatment of Parkinson's disease, hyperprolactinemia and migraine.
  • the drug may be administered twice a day at a daily dosage of about 10 to about 60 mg, preferably about 20 to about 40 mg.
  • compositions of the present invention are typically hydrophilic polymers, such as gums, cellulose ethers and protein derived materials.
  • these hydrophilic polymers may include hydroxyalkylcelluloses, polyvinyl alcohols, polyoxyethylene glycols and poloxamers.
  • Preferred hydroxyalkylcelluloses include methylcellulose, carboxymethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose.
  • the most preferred hydrophilic swelling substance is hydroxypropylmethylcellulose.
  • Hydroxypropylmethylcelluloses that may be used in the present invention include Methocel K4M® and Methocel K15M®, both commercially available from Colorcon of West Point, Pennsylvania. Methocel K4M® and Methocel K15M® have a 19-24 weight percent methoxyl content and a 4-12 weight percent hydroxypropyl content. Methocel K4M® in a 2% water solution has a viscosity of 4,000 cps and an average molecular weight of 89,000, while Methocel K15M® in the same conditions has a viscosity of 15,000 cps and an average molecular weight of 124,000.
  • Formulations of the present invention also contain excipients.
  • excipients include lubricants, suspending agents, binders, diluents, flavorants, colorants, dispersing agents and wetting agents, the use of which will be known to those skilled in the art.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, microcrystalline cellulose, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum and/or polyvinylpyrrolidone (PVP); and lubricants such as magnesium stearate.
  • fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol
  • cellulose preparations such as, for example, microcrystalline cellulose, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum
  • Formulations of the present invention preferably contain about 5 to about 80 mg of ergot peptide alkaloids.
  • the ratio of ergot peptide alkaloid to swelling substance is preferably from about 1:0.5 to about 1:10, more preferably from about 1:2 to about 1:8.
  • the ratio of dihydroergocriptine to swelling substance is from about 1:0.5 to about 1:5, more preferably from about 1:1 to about 1:4.
  • the ratio of ergot peptide alkaloid to excipients is preferably from about 1:3 to about 1:100, more preferably from about 1:5 to about 1:80 and most preferably from about 1:10 to about 1:50.
  • Formulations of the present invention provide an increase in bioavailability over other sustained-release formulations. More importantly, formulations of the present invention provide an increase in bioavailability over conventional formulations.
  • the bioavailability of formulations of the present invention is preferably at least about 5%, more preferably at least about 15%, and most preferably at least about 25% higher than the bioavailability of conventional formulations.
  • the formulations of the present invention may be prepared according to conventional methods by blending together the drug and all the excipients except the lubricant to form a blended powder.
  • the powder is mixed with the lubricant and the resultant powder is pressed to form a tablet.
  • composition of each tablet ⁇ -Dihydroergocryptine 20.0 mg Cellactose® 203.0 mg Methocel K15M® 25.0 mg Syloid 244® 1.2 mg Magnesium stearate 0.8 mg
  • Tablets (250 mg) containing 20 mg (8%) each of ⁇ -dihydroergocryptine were prepared with 80% of Cellactose®, as direct compressible excipient, 10% of Methocel K15M® , as swellable controlled release polymer, 1.2% of Syloid 244®, as free flowing agent, and 0.8% of magnesium stearate, as lubricant.
  • the drug and all excipients except the lubricant were geometrically blended manually with a sieve, then mixed with a Turbula mixer for 10 minutes. After adding magnesium stearate, the mixture was blended for another 5 minutes.
  • composition of each tablet ⁇ -Dihydroergocryptine 20.0 mg Methocel K4M® 13.2 mg Sodium CMC 26.8 mg Lactose 48.0 mg PVP K30 6.7 mg Talc 4.0 mg Magnesium stearate 1.3 mg
  • Tablets 120 mg containing 20 mg (16.7%) each of ⁇ -dihydroergocryptine were prepared and tested according to the methods described hereafter.
  • the formulation was prepared with 40% of lactose, as diluent, 11% of Methocel K4M® and 22.3% of Sodium CMC (medium viscosity), as swellable controlled release polymers, 5.6% of PVP, as binding agent, 3.3% of talc, as anti-sticking agent, and 1.1% of magnesium stearate, as lubricant.
  • a 10% water solution of PVP was prepared.
  • the drug, the diluent and the polymers were mixed coarsely.
  • the water solution of PVP was added to the powder mix to form a wet mass, which was screened successively through 8 mesh screen.
  • the wet granulate was dried at 60°C, then screened again through 16 mesh screen.
  • After adding talc and magnesium stearate, the mixture was blended for five minutes in a V mixer.
  • composition of each tablet ⁇ -Dihydroergocryptine 40.0 mg Lactose DCL11® 92.5 mg Avicel PH101® 76.0 mg Methocel K4M® 37.5 mg Magnesium stearate 4.0 mg
  • Tablets (250 mg) containing 40 mg (16%) each of ⁇ -dihydroergocryptine were prepared and tested according to the methods described hereafter.
  • the formulation was prepared with 37% of lactose and 30.4% of microcrystalline cellulose, as direct compressible excipients, 15% of Methocel K4M® , as swellable controlled release polymer, and 1.6% of magnesium stearate, as lubricant.
  • the drug and all excipients except the lubricant were geometrically blended manually with a sieve, then mixed with a Turbula mixer for 10 minutes. After adding magnesium stearate, the mixture was blended for another 5 minutes.
  • a rotary 8 station laboratory press with automatic powder feed and capsular tools (12 x 5 mm) was used for compression.
  • composition of each tablet ⁇ -Dihydroergocryptine 40.0 mg Lactose DCL11® 105.0 mg Avicel PH101® 76.0 mg Carbopol 934P® 25.0 mg Magnesium stearate 4.0 mg
  • Tablets (250 mg) containing 40 mg (16%) each of ⁇ -dihydroergocryptine were prepared and tested according to the methods described hereafter.
  • the formulation was prepared with 42% of lactose and 30.4% of microcrystalline cellulose, as direct compressible excipients, 10% of carbomer, as swellable controlled release polymer, and 1.6% of magnesium stearate, as lubricant.
  • the drug and all excipients except the lubricant were geometrically blended manually with a sieve, then mixed with a Turbula mixer for 10 minutes. After adding magnesium stearate, the mixture was blended for other 5 minutes.
  • a rotary 8 station laboratory press with automatic powder feed and capsular tools (12 x 5 mm) was used for compression.
  • composition of each tablet ⁇ -Dihydroergocryptine 10.0 mg Cellactose® 184.3 mg Methocel K4M® 22.0 mg Methocel K15M® 9.7 mg Sodium CMC 2.0 mg Talc 20.0 mg Magnesium stearate 2.0 mg
  • Tablets (250 mg) containing 10 mg (4%) each of ⁇ -dihydroergocryptine were prepared and tested according to the methods described hereafter.
  • the formulation was prepared with 73.3% of Cellactose®, as direct compressible excipient, 8.8% of Methocel K4M®, 3.9% of Methocel K15M® and 0.8% of sodium CMC as swellable controlled release polymers, 8% of Talc, as anti-sticking agent, and 0.8% of magnesium stearate, as lubricant.
  • the drug and all excipients except the lubricant were geometrically blended manually with a sieve, then mixed with a Turbula mixer for 10 minutes. After adding magnesium stearate, the mixture was blended for other 5 minutes.
  • a rotary 8 station laboratory press with automatic powder feed and capsular tools (12 x 5 mm) was used for compression.
  • composition of each tablet ⁇ -Dihydroergocryptine 10.0 mg Cellactose® 216.0 mg Methocel K4M® 15.0 mg Methocel K15M® 5.0 mg Sodium CMC 2.0 mg Magnesium stearate 2.0 mg
  • Tablets (250 mg) containing 10 mg (4%) each of ⁇ -dihydroergocryptine were prepared and tested according to the methods described hereafter.
  • the formulation was prepared with 86.4% of Cellactose®, as direct compressible excipient, 6% of Methocel K4M®, 2% of Methocel K15M® and 0.8% of sodium CMC as swellable controlled release polymers, and 0.8% of magnesium stearate, as lubricant.
  • the drug and all excipients except the lubricant were geometrically blended manually with a sieve, then mixed with a Turbula mixer for 10 minutes. After adding magnesium stearate, the mixture was blended for another 5 minutes.
  • a rotary 8 station laboratory press with automatic powder feed and capsular tools (12 x 5 mm) was used for compression.
  • Tablets (250 mg) containing 5 mg (2%) each of bromocriptine were prepared and tested according to the methods described hereafter.
  • the formulation was prepared with 75.7% of Cellactose®, as direct compressible excipient, 8.8% of Methocel K4M®, 3.9% of Methocel K15M® and 0.8% of sodium CMC as swellable controlled release polymers, 8% of Talc, as anti-sticking agent, and 0.8% of magnesium stearate, as lubricant.
  • the drug and all excipients except the lubricant were geometrically blended manually with a sieve, then mixed with a Turbula mixer for 10 minutes. After adding magnesium stearate, the mixture was blended for another 5 minutes.
  • a rotary 8 station laboratory press with automatic powder feed and capsular tools (12 x 5 mm) was used for compression.
  • the objective of the study was to evaluate in healthy volunteers the pharmacokinetic characteristics and the bioavailability of ⁇ -dihydroergocryptine in oral sustained-release tablets according to the present invention as described in Examples 5 and 6 in comparison to a conventional tablet according to the conventional tablet formulation described under Example 5.
  • the study design was an open label, crossover, 3 period design. Twelve male volunteers were randomly assigned to one of three treatment sequences, separated by a one-week wash-out period. The drug was administered orally in the morning in fasted conditions (the fasted conditions were maintained for 4 hours after treatment) in a single dosage of 10 mg. Blood samples were obtained by an indwelling cannula at specific time points up to 72 hours after administration of the drug.
  • a three-fold increase of the elimination half-life is observed for the sustained-release formulation described in Example 6, an index of a prolonged absorption process as compared to the conventional tablet.
  • the bioavailability of sustained release formulations of the present invention, as measured by AUC, is surprisingly higher than the bioavailability obtained with the conventional tablet.

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EP00985142A 1999-12-03 2000-11-30 Methods for making sustained-release pharmaceutical compositions of ergot alkaloids having improved bioavailability and compositions thereof Expired - Lifetime EP1235574B1 (en)

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PCT/EP2000/012302 WO2001039742A2 (en) 1999-12-03 2000-11-30 Methods for making sustained-release pharmaceutical compositions of ergot alkaloids having improved bioavailability and compositions thereof

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WO2004082615A2 (en) * 2003-03-14 2004-09-30 Nirmal Mulye A process for preparing sustained release tablets
US20050095292A1 (en) * 2003-10-29 2005-05-05 Wyeth Sustained release pharmaceutical compositions
RU2382648C2 (ru) * 2004-12-03 2010-02-27 Мерк Энд Ко., Инк. Фармацевтический состав карбоксамидных ингибиторов интегразы вич, содержащий композицию с контролируемой скоростью высвобождения
US20100035886A1 (en) 2007-06-21 2010-02-11 Veroscience, Llc Parenteral formulations of dopamine agonists
US8741918B2 (en) * 2007-06-21 2014-06-03 Veroscience Llc Parenteral formulations of dopamine agonists
CN101590058B (zh) * 2009-07-02 2011-04-27 苏州东瑞制药有限公司 含有甲磺酸二氢麦角隐亭a的药物组合物

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CA2393344C (en) 2009-09-01
ATE288269T1 (de) 2005-02-15
US20020114836A1 (en) 2002-08-22
WO2001039742A3 (en) 2001-12-13
PL356387A1 (en) 2004-06-28
JP4965784B2 (ja) 2012-07-04
DE60017938T2 (de) 2006-01-12
BR0016084A (pt) 2002-08-06
AU2165301A (en) 2001-06-12
PT1235574E (pt) 2005-05-31
MXPA02005291A (es) 2004-06-21
JP2003515549A (ja) 2003-05-07
RU2002117655A (ru) 2004-01-27
CA2393344A1 (en) 2001-06-07
KR20020063197A (ko) 2002-08-01
KR100504618B1 (ko) 2005-08-04
HK1048254A1 (en) 2003-03-28
PL202357B1 (pl) 2009-06-30
HK1048254B (zh) 2005-06-03
DE60017938D1 (de) 2005-03-10
CN1433311A (zh) 2003-07-30
WO2001039742A2 (en) 2001-06-07
CN100400042C (zh) 2008-07-09
ES2236017T3 (es) 2005-07-16
EP1235574A2 (en) 2002-09-04
EP1512403A1 (en) 2005-03-09

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